NH_12CBT_Research.pdf

Neuropsychological Effects of Cognitive Behavioral Therapy I. Neuropsychological effects of Cognitive Behavioral Therapy A. OCD B. Depression − Comparison with effects of pharmacotherapy C. PTSD D. Phobias II. Use of neuroimaging in diagnosis and treatment of psychological disorders III. New rese...

Neuropsychological Effects of Cognitive Behavioral Therapy I. Neuropsychological effects of Cognitive Behavioral Therapy A. OCD B. Depression − Comparison with effects of pharmacotherapy C. PTSD D. Phobias II. Use of neuroimaging in diagnosis and treatment of psychological disorders III. New research on optogenetic treatment of depression CBT for Specific Psychological Disorders CBT for OCD • OCD is characterized by unwanted repetitive thoughts and unwanted, repetitive behaviors • Jeffrey Schwartz’s CBT technique for treatment of OCD has roots in mindfulness practice: − Attend “just to the bare facts of a perception as presented either through the five physical senses or through the mind…without reacting to them by deed, speech or by mental comment” − This means learning to experience an OCD symptom without reacting emotionally, learning to realize that the feeling that something is amiss is just the manifestation of overactivity in the OCD circuit (Schwartz & Begley, 2002) o Ex: A patient would think, “My OCD circuit is producing another obsessive thought. I know it’s not real but just static from a faulty circuit.” ➜ Patients reported that obsessive thoughts no longer controlled them ☛ Client with Obsessive-Compulsive Disorder (OCD) is taught to: 1) Relabel: identify what’s real and what isn’t and refuse to be misled by obsessive thoughts “That compulsion is bothering me again,” rather than “I feel like I need to wash my hands again” 2) Reattribute: you understand that those thoughts and urges are merely false messages being sent from your brain “That compulsion is bothering me because I have a medical condition called OCD that is related to a biochemical imbalance in my brain” 3) Refocus: turn your attention to more constructive behavior, knowing that by doing so, you are actually changing the way your brain works in an extremely healthy and wholesome way 4) Revalue: you come to see compulsions and obsessive thoughts as the useless garbage they really are as soon as they arise Ø Research has indicated that OCD is characterized by hyperactivity in two regions: • Orbitofrontal: serves to identify when something is amiss • Striatum, in particular, the caudate nucleus: involved in execution of motor behavior with inputs from the orbitofrontal, as well as the amygdala • Together, these areas form what has been called the “worry circuit” ➜ In people with OCD this circuit is buzzing with activity Ø Early PET studies found that, after course of CBT, • Metabolic activity of a caudate–orbital–thalamic brain circuit fell dramatically • Degree of alteration was associated with a positive treatment response to CBT • Effect was similar to that produced by pharmacotherapy (with SSRI) (Baxter, Schwartz, Bergman et al., 1992; Schwartz, Stoessel, Baxter et al., 1996) Ø Follow-up PET-fMRI study demonstrated that • OCD symptoms, depression, anxiety and overall functioning improved robustly with treatment after just 4 weeks of CBT treatment • Degree of improvement in OCD symptoms correlated with increase in right dorsal anterior cingulate cortex activity − The dACC is involved in reappraisal and suppression of negative emotions ☞ Research on OCD was among the first to show that thinking about thoughts in a new way can alter patterns of brain activity (Saxena, Gorbis, O’Neill et al., 2009) ☛CBT for major depressive disorder (MDD) Patients learn to • Recognize their habit of catastrophizing, of turning everyday setbacks into calamities v “The fact that she didn’t want to go out with me a second time means I am a total loser and will never be loved” • Regard these types of depressive thoughts as simple electrical events in the brain (similar to CBT for OCD) • Simply feel the sadness and experience the disappointment without allowing those thoughts to elaborate (mindfulness component) Review article (Frewen, Dozois, Lanius et al., 2008) concluded that participation in CBT or IPT (Interpersonal Therapy, which focuses on improving people’s current relationships) for depression is associated with changes in brain metabolic activity in depressed individuals • These changes varied depending on − The specific psychological interventions (IPT vs. CBT) − Neuroimaging methods used − Length of follow-up periods • However, some consistent findings also emerged across the studies: therapy outcomes were primarily associated, during an awake state at rest, with altered functioning in − Dorsolateral prefrontal cortex o Important in executive function, working memory, and cognitive flexibility o Altered function may reflect improved problem-solving (more effective coping with life stress) or reduction in worrying and associated negative affect − Ventrolateral prefrontal regions, particularly within the right hemisphere; anterior and posterior cingulate; and medial prefrontal regions o May reflect improved affect regulation and self-perception − Was there increased or decreased function in these areas? ➜ Interestingly, there were conflicting findings on that question It is difficult to characterize the function(s) of a particular brain region because • The same brain areas are active in many different tasks • Each task results in activation in several areas (Genon, Reid, Langner et al., 2018) In addition, research seems to indicate that • There are different pathways for resolving issues related to emotional dysregulation • Different types of therapy might utilize different pathways Ø Study on patients with major depression (Goldapple, Segal, Garson et al., 2004) • Participants were given 15-20 sessions of CBT using behavioral activation, cognitive monitoring, and other techniques Results: • Therapy resulted in significant clinical improvement as indicated by Hamilton Depression Rating Scale and Beck Depression Inventory • PET analysis performed before and after treatment revealed that treatment resulted in − Decreased activation in dorsal, ventral, and medial frontal cortex − Increased activation in hippocampus and dorsal cingulate ➜ Patients reported that they ruminated less and no longer felt emotionally dead inside In contrast, other studies have demonstrated that patients treated with Paxil (SSRI) showed • Increased activation in prefrontal • Decreased activation in hippocampus and subgenual cingulate ☞ Both types of treatments result in a net change in critical prefrontalhippocampal pathways, but the changes were in opposite directions! − Proposed explanation is that it is the overall modulation of this complex system rather than any one focal regional change that may be most critical for disease remission In case of CBT for depression • Reduction in medial frontal activity may be associated with reduction in rumination • Increased hippocampal activity may be associated with increased attention to environmental stimuli and sensitivity to context The frontal decreases seen with CBT are similar to those reported with a PET study on Interpersonal Therapy (IPT) (Brody, Saxena, Stoessel et al., 2001) • IPT focuses on improving people’s current relationships – more on that in Social Relationships lecture Previous studies have found that depression is associated with exaggerated activity in the medial prefrontal (Elliott, Rubinsztein, Sahakian et al., 2002) • Reduction in activity in these regions may reflect a reduced bias toward the processing of negative information in the recovered state, with implications for future relapse risk • The above may explain the finding – which appears in a large number of studies – that CBT treatment alone more effectively prevents relapse than antidepressant medication treatment alone (Cuijpers, Hollon, van Straten et al., 2010; Zhang, Zhang, Zhang et al., 2018; Dobson, Hollon, Dimidjian et al., 2008 ) Effects of placebos on brain activity • The placebo effect is considered by some to be a psychological form of treatment • Interestingly though, the brain changes associated with placebos tend to directly shadow the true drug-response pattern (De la Fuente-Fernandez R, Ruth TJ, Sossi et al., 2001; Petrovic P, Kalso E, Petersson et al., 2002) Ø Fluoxetine (Prozac) treatment for depression is associated with − Increased activity in the frontal cortex − Decreased activity in the subgenual cingulate CBT for PTSD Ø Study on patients diagnosed with either major depression or PTSD ➜ Relative to controls, CBT-treated patients had significantly increased connectivity of the amygdala with the frontoparietal network following CBT Red = Increased activation Blue = Decreased activation (Shou, Yang, Satterthwaite et al., 2017) ✧ As mentioned earlier, PTSD is associated with a reduction in hippocampal volume ✧ A number of studies have found that CBT treatment for PTSD, as well as pharmacotherapy, is associated with • Increased hippocampal volume • Decreased amygdala activation • Increased dorsolateral prefrontal activation (Thomas, Dorrepaal, Drijer et al., 2014) Ø Ex: PTSD patients were given trauma-focused CBT (TF-CBT) in which participants learn how to identify dysfunctional automatic thoughts and cognitive distortions, find evidence for and against thoughts, and create alternatives • At baseline, relative to controls, MRI analysis showed that patient group had − Lower expression of glucocorticoid receptor genes known as FKBP5 − Smaller hippocampus • After treatment, patients showed − Increased hippocampal volume − Increased FKBP5 gene expression ➜ Improvement in PTSD symptoms was predicted by both of the above, but particularly by FKBP5 gene expression (Levy-Gigi, Szabo, Kelemen et al., 2013) CAPS = Clinician-Administered PTSD Scale CBT for phobias Ø Study on patients with spider phobia • Phobia was assessed using surveys and direct confrontation with spiders • fMRI was performed pre- and post-therapy • Therapy consisted of − Gradual exposure-based treatment to spiders using guided mastery − Education for correcting misbeliefs about spiders • fMRI indicated that during viewing of films depicting spiders − Pre-treatment, compared to controls, patients had significant activation of o Right dorsolateral prefrontal cortex (may reflect attempts to self-regulate triggered fear) o Parahippocampal gyrus (might be related to an automatic reactivation of the contextual fear memory that led to the development of phobia) − After successful completion of CBT, no significant activation was found in the dorsolateral prefrontal cortex or the parahippocampal gyrus (Paquette, Levesque, Mensour et al., 2003) v Some studies, such as preceding one on spider phobia only used female participants as a way of minimizing variation in brain activity during reappraisal v Unclear what implications might be for generalization to male population as solid research on gender differences in response to CBT is limited at this point Tailoring Treatment Based on Neuroimaging Data Research is nearing the point where we may be able to tailor treatment for psychological disorders based on neuroimaging data Obsessive-compulsive disorder Ø PET study (Brody, Saxena, Schwartz et al., 1998) of OCD patients found that • Those who responded to behavioral therapy showed higher metabolism in left frontal orbital cortex before treatment • On the other hand, lower metabolic activity in left frontal orbital cortex was associated with better response to fluoxetine (Prozac) treatment Social anxiety disorder Ø Differences in brain structure and neural connectivity among different regions predicted how well CBT reduced symptoms of those with social anxiety disorder ➜ Estimates of treatment outcome were five times more accurate than estimates using a behavioral assessment tool alone (Whitfield-Gabrieli, Ghosh, Nieto-Castanon et al., 2015) Ø Participants with social anxiety disorder were asked to identify letters behind which occasionally lurked pictures of angry faces ➜ Those who struggled most to avoid being distracted by the threatening stimuli—indicated by more activity in dorsal anterior cingulate cortex—showed the most symptom improvement when treated with CBT (Klumpp, Fitzgerald, Piejko et al, 2015) Depression Ø One study found that people whose depression improved most after behavioral activation therapy had greater brain network connectivity between − The anterior insular cortex (involved in assigning importance to events) and − The middle temporal gyrus (involved in subjective experience of emotion) (Crowther, Smoski, Minkel et al., 2016) Recently many neuroimaging studies have been published on biomarkers for treatment response and recurrence of depression using various methods, including • Volumetric MRI • fMRI (while participants were in resting-state or engaged in affective tasks) • Diffusion tensor imaging or DTI However, the results have been inconsistent, and a review article (Kang & Cho, 2020) hypothesized that this could be due to • Small sample size • Different study designs, including eligibility criteria • Differences in the imaging and analysis techniques ➜ More research is clearly needed in this area with larger sample size, using a research design that includes a more comprehensive integration of techniques In addition, new research has emerged that aims to treat major depression by optogenetically reactivating neurons associated with positive memories Ø Male mice were exposed to a pleasurable experience (spending time with female mice) • Cells in the hippocampus that encoded the memory engram were labeled using optogenetics • Researchers then induced depression-like symptoms in the mice by exposing them to chronic stress • Mice showed symptoms that mimic those of human sufferers of depression, such as giving up easily when faced with a difficult situation and failing to take pleasure in activities that are normally enjoyable ➜ When cells in dentate gyrus of hippocampus that were previously active during the positive experience were reactivated, symptoms improved dramatically— but only for as long as the pleasant memory stayed activated (Ramirez, Liu, MacDonald et al., 2015) Ø Follow-up study • Pleasant memory was reactivated 15 minutes, twice a day, for five days • This time, though the memories were not reactivated during the behavioral tests for depression, the mice − Behaved like mice that had never been depressed (!) − Experienced an increase in neurogenesis ➜ Glutamatergic activity in the hippocampus-amygdala-nucleus accumbens pathway was identified as a probable circuit supporting improvement Interestingly, the researchers found that allowing the mice to engage in pleasurable experiences after becoming depressed did not improve their symptoms nearly as much as reactivating an old memory • This is probably because if you give a natural positive experience to the person or the animal, the depression that they have prevents them from finding that experience rewarding Can this be done in humans? Not at present ✧ Challenges: • With optogenetics, cells need to be genetically engineered to produce opsins − In mice, this is done through microinjection of viruses to insert specific genes that will cause cell to express channelrhodopsin − Microinjection of viruses into human brain has been done for treatment of Parkinson disease and Alzheimer’s disease, but it is a highly invasive procedure − Newer genetic engineering technologies, such as TAT-mediated protein transduction or liposome-mediated plasmid transfection, may potentially be adapted for nonviral delivery of channelrhodopsin to neurons • Implantation of a light fibre with an adaptor to interface with a laser is also required − Less invasive than implantation of an electrode but still considered risky − Alternatives: o Light stimulation via the aural canal o Use of near-infrared transcranial stimulation, but that would require engineering a channelrhodopsin that is responsive to that light wavelength ➜ No real breakthroughs yet in use of optogenetics in humans though technique has helped to elucidate brain circuits involved in mental illnesses, like depression